Could This Be the First Stage of Schizophrenia? Early Origins of Schizophrenia: The Intriguing Pre-Brain Influences

It is commonly believed that genetic and external risk factors only play a direct part in the brain when it comes to schizophrenia, but these new findings show that the health of this organ is also important.

A recent study led by the Lieber Institute for Brain Development suggests that over 100 genes associated with the risk of schizophrenia may contribute to the development of the illness through their involvement in the placenta, rather than primarily affecting the developing brain.

Traditionally, scientists have long believed that genes linked to schizophrenia primarily influenced the brain.

However, the latest research, published in Nature Communications, reveals that the placenta plays a significantly larger role in the development of the illness than previously recognized.

“The secret of the genetics of schizophrenia has been hiding in plain sight—the placenta, the critical organ in supporting prenatal development, launches the developmental trajectory of risk,” points out senior author Daniel Weinberger.

The study revealed a significant correlation between schizophrenia genes and the crucial role of the placenta in detecting nutrients, such as oxygen, within the mother’s bloodstream. These genes affect the expression levels in trophoblasts, the core cells responsible for maternal-fetal nutrient exchange, resulting in an adverse impact on the placenta’s ability to support the developing fetus.

Furthermore, the research paper identified several placental genes that contribute to the development of various disorders, including diabetes, bipolar disorder, depression, autism, and attention deficit hyperactivity disorder (ADHD). Notably, the study uncovered a higher number of genetic associations between schizophrenia genes and the placenta compared to these other disorders.

Additionally, the researchers made an intriguing observation regarding the heritability of schizophrenia risk genes found in the placenta. They found that these genes might have a relatively stronger influence on the likelihood of inheriting the illness from ancestors compared to risk genes identified in the brain.

“Targeting placenta biology is a crucial new potential approach to prevention, which is the holy grail of public health,” notes lead author Gianluca Ursini. “Scientists could detect changes in placental risk genes decades before the possible onset of a disorder, possibly even in the mother’s bloodstream during pregnancy. If doctors knew which children were most at risk of developmental disorders, they could implement early interventions to keep them healthy.”

The study also revealed intriguing variations based on the sex of the child in relation to placental risk genes. Depending on whether the placenta originated from a male or female child, different genes were associated with the risk of schizophrenia. In pregnancies with male children, inflammatory processes in the placenta appeared to play a central role. Previous research has shown that males are more susceptible to prenatal stress compared to females. It is worth noting that developmental disorders like schizophrenia tend to occur more frequently in men and boys.

Furthermore, the research yielded concerning findings concerning pregnancies affected by COVID-19. By examining a small sample of placentas from mothers who contracted COVID-19 during pregnancy, the scientists observed a significant activation of schizophrenia-related genes associated with placental risk.

This discovery suggests that COVID-19 infection during pregnancy might be a contributing factor for schizophrenia, primarily due to its impact on the placenta.

The Lieber Institute researchers are currently conducting NIH-funded research to explore this possibility further by analyzing placentas from COVID-19-affected pregnancies.

The ongoing investigation of placental genes by the Lieber Institute holds the potential to pave the way for innovative treatment and diagnostic tools, which could potentially revolutionize the field of prenatal medicine. The researchers aspire to uncover new avenues for understanding and addressing prenatal conditions based on their comprehensive study of placental genetics.

“In the modern era of molecular and genetic medicine, the standard treatment for a complicated pregnancy is still primarily bedrest,” adds Dr. Weinberger. “These new molecular insights into how genes related to disorders of the brain and other organs play out in the placenta offer new opportunities for improving prenatal health and preventing complications later in life.”   

Source: 10.1038/s41467-023-38140-1

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